Propionic Acidemia · PA

Description

Propionic acidemia (PA) is an autosomal recessive organic acid disorder. The enzyme propionyl-CoA carboxylase, a mitochondrial biotin-dependent enzyme made of alpha and beta subunits encoded by PCCA on chromosome 13 and PCCB on chromosome 3, converts propionyl-CoA to methylmalonyl-CoA. Two damaging copies of either subunit gene reduce or abolish enzyme activity. Propionyl-CoA and its derivatives (propionic acid, 3-hydroxypropionate, methylcitrate, propionylcarnitine) accumulate, the resulting organic acidemia drives metabolic decompensation, and secondary inhibition of the urea cycle produces hyperammonemia.

Affected newborns typically present in the first days to weeks of life with poor feeding, vomiting, lethargy, hypotonia, tachypnea, and progression to coma if untreated. Ammonia is often markedly elevated. Survivors of the neonatal crisis face a chronic course with recurrent metabolic decompensations triggered by infection or catabolic stress, failure to thrive, and developmental delay. Late complications across cohorts include cardiomyopathy (dilated and less commonly hypertrophic), prolonged QT interval and other arrhythmias, optic atrophy, basal-ganglia injury producing movement disorders, pancreatitis, and chronic kidney disease. Cardiomyopathy is a leading cause of death in adolescents and young adults with PA.

Detection is by newborn screening on the dried blood spot using tandem mass spectrometry, which flags elevated propionylcarnitine (C3) and an elevated C3 to acetylcarnitine (C2) ratio, the same screening signal used for methylmalonic acidemia. Confirmation uses urine organic acids showing 3-hydroxypropionate, methylcitrate, and propionylglycine, plasma acylcarnitines, plasma amino acids, and PCCA or PCCB sequencing. Reported incidence in US and European newborn screening programs is roughly 1 in 100,000 to 1 in 150,000 live births. Higher incidence has been documented in several founder populations, including the Greenlandic Inuit and parts of the Saudi Arabian population, attributed to specific founder variants and high consanguinity.

Treatments to date

Standard of care is lifelong protein-restricted diet using medical formula free of isoleucine, valine, methionine, and threonine, paired with measured natural protein, calorie support, and L-carnitine supplementation to clear propionyl groups as propionylcarnitine. Oral metronidazole or an alternative antibiotic is used in some centers to suppress propionate production by gut bacteria. Sick-day protocols use high-calorie low-protein intake, and acute decompensations are managed with intravenous dextrose, insulin when needed, ammonia scavengers including sodium phenylbutyrate or sodium benzoate, carglumic acid for hyperammonemia, and hemodialysis for severe acidosis or refractory hyperammonemia. Carglumic acid (Carbaglu) was approved by the FDA in 2010 for N-acetylglutamate synthase deficiency and gained an additional indication in 2021 for adjunctive treatment of acute hyperammonemia in propionic acidemia and methylmalonic acidemia. Cardiac surveillance with echocardiography and electrocardiography is part of routine follow-up.

No FDA-approved disease-specific drug exists for the underlying enzymatic defect. Liver transplantation, alone or combined with kidney transplantation, is offered at multiple centers and reduces metabolic crises, although residual extrahepatic disease and risk of cardiomyopathy persist because the enzyme is required throughout the body. mRNA replacement therapy is in clinical development; Moderna's mRNA-3927 program, encoding both PCCA and PCCB subunits in a single lipid nanoparticle delivery, entered Phase 1/2 trials in 2022. AAV-delivered gene therapy programs are in earlier preclinical and clinical stages.